Multicellular organisms use a process called apoptosis to instruct damaged or unnecessary cells to destroy themselves for the good of the organism. Control of the apoptotic process is very important to the normal development of the organism. For example, development of fetal fingers and toes requires the controlled removal, by apoptosis, of excess interconnecting tissues, as does the proper formation of neural synapses within the brain. Similarly, controlled apoptosis is responsible for the sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation.
Apoptosis not only plays an important role in tissue sculpting during development and normal cellular maintenance, it is also the primary defense against cells that pose a threat to the well being of the organism. In the cell-mediated immune response, effector cells (e.g., cytotoxic T lymphocytes “CTLs”) destroy virus-infected cells by inducing the infected cells to undergo apoptosis. The organism subsequently relies on the apoptotic process to destroy the effector cells when they are no longer needed. The CTLs induce apoptosis in each other and even in themselves thus preventing autoimmunity. Defects in this process are associated with a variety of debilitating autoimmune diseases such as lupus erythematosus and rheumatoid arthritis.
Normally, multicellular organisms also use the apoptotic process to instruct cells with damaged nucleic acids (e.g., DNA) to destroy themselves prior to becoming cancerous. However, some cancer-causing viruses prevent infected cells from initiating the apoptotic process. Two human papilloma viruses (HPV) have been implicated in causing cervical cancer by suppressing apoptotic removal of transformed cells by producing a protein (E6) that inactivates the p53 apoptosis promoter. Epstein-Barr virus (EBV), the causative agent of mononucleosis and Burkitt's lymphoma a solid tumor of B lymphocytes, produces a protein similar to Bcl-2 and another that causes infected cells to increase production of Bcl-2. Both of these mechanisms make the Epstein-Barr virus infected cells resistant to apoptosis thus allowing the cancerous cells to proliferate and to spread throughout the organism.
Some cancers that arise by non-viral means have also developed mechanisms to escape destruction by apoptosis. Melanoma cells, for instance, avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1. Other cancer cells, especially lung and colon cancer cells, secrete elevated levels of soluble decoy molecules that bind to FasL, inhibiting it from binding to Fas. CTLs are thus prohibited from destroying these protected cancer cells. Other cancer cells express high levels of FasL, again, avoiding destruction by the CTLs. Still other viruses manipulate the cell's apoptotic machinery without directly resulting in the development of a cancer. For example, destruction of the immune system in individuals infected with the human immunodeficiency virus (HIV) progresses by infected CD4+ T cells (about 1 in 100,000) instructing uninfected CD4+ T cells to undergo apoptosis.
Various degenerative conditions and vascular diseases may also result from faulty regulation of the apoptotic machinery.
It is apparent that the controlled regulation of the apoptotic process and the apoptotic machinery is vital to the survival of multicellular organisms. Typically, the biochemical changes that occur in a cell instructed to undergo apoptosis occur in an orderly procession. However, as shown above, flawed regulation of the apoptotic process and machinery can cause serious deleterious effects and diseases to arise in an organism.
There have been various attempts to control and restore regulation of the apoptotic machinery in aberrant cells (e.g., cancer cells). Generally, these attempts have had limited success as treatments for the underlying diseases characterized by the faulty regulation of the apoptotic machinery for a number of reasons, such as, toxicity, ineffectiveness, high costs, and the like. The art needs improved compositions and methods of regulating apoptosis in subjects afflicted with diseases and conditions characterized by faulty regulation of the apoptotic process.